The Fetus And Birth - .e-bookshelf.de

2G.S. DAWESAt the same time, in thle period after the Second World War, iiivestigationswere started by Arpad Csapo and his colleagues on the action of drugs on theuterus in experimental animals, and by Jean Marshall, Brenda Schofield andDavid Porter, and by Roberto Caldeyro-Barcia, Fritz and Anna-Riita Fuchs andCarl Wood, in animals and man, to mention only a few names. These observations provided a description of the natural phenomena in several species and arational background on which to build. But the theories of that epoch, with theirvivid imagery, their emphasis on changes in natural motility and the ‘braking’effect of progesterone, seemed to the observer on the side-lines still somewhatremote. There was a large gap between the hormonal events, as known in thelate 1950s, and the electrical or mechanical phenomena associated with myometrial activity in vivo or in vitro. Yet the first steps had been taken, a corpusof knowledge had been assembled, controversies flourished on the relativeimportance of oestrogens and progesterone, and their relation to oxytocin, andled to more experiments.In December 1963 the American Institute of Biological Sciences held aconference on the Initiation of Labor sponsored by the National Institute ofChild Health and Human Development, which marks a watershed in thedevelopment of the subject. Among the work reviewed were observations madeby Kennedy, Binns and others (Holm 1963) on natural variations in the durationof gestation. Thus in some Holstein-Friesian and Guernsey cows, in sheepexposed to the toxic effects of Veratrum californicum in Idaho, and in Karakulewes in South-West Africa, abnormally prolonged pregnancy was associatedwith defects of the fetal pituitary. The work of Binns and his colleagues (1964),in which the defect was produced by feeding the toxic material to sheep, is ofspecial interest. Conversely, van Rensburg (Holm 1963) had reported abnormallyshort pregnancies in Angora goats with hyperplastic fetal adrenals. The stagewas thus set for the remarkable direct experimental demonstration by MontLiggins (Liggins 1969; Liggins et al. 1967) that in sheep the fetal pituitary andadrenal cortex play a preponderant part in the determination of the timing oflabour.The technical advances of the period included new skills in fetal surgery.Blood samples were withdrawn and drugs injected through the new types ofplastic catheters. The preparations benefited from advances in antibiotic therapyand anaesthesia. The paper by Holm & Short (1962) in which they reported theprogesterone concentration in the peripheral blood of five Guernsey or Friesiancows with prolonged pregnancy mentioned blood samples of ‘about one litre’that were collected. There have been remarkable advances since that date in thesensitivity and specificity of immunoassay.Above all the discovery of the prostaglandins, with their role in the control

INTRODUCTION3of several aspects of reproductive endocrinology and as a link between thesteroid hormones and the cells of the myometrium, has been one of the mostimportant contributions to the subject.The timing of this symposium in 1976 is deliberate. It is now ten years sinceMont Liggins started the experiments in Auckland, New Zealand, which provided experimental evidence for the part normally played by the fetal lamb inthe initiation of labour. He gave a brief account of this work at the CibaFoundation Symposium on Foetal Autonomy in 1969, the same year as Dr Csapotook the chair at a Ciba Foundation Study Group on Progesterone: its regulatoryeffect on the myoinetrium. We are now going to try to synthesize these approaches.During the symposium we may ask several types of question. First, is thecurrent account of the fetal control of parturition in the sheep and goat whollysatisfactory? Are there steps missing, for example in the means whereby thefetus controls cortisol release either by a central nervous mechanism or peripherally? Are the enzymes of the fetal adrenal cortex mature early in gestation?Is the concept of a fetoplacental unit secure in this species, or is oestrogenwholly derived from the placenta? Where does it act? Are we satisfied that theconnecting link in these species between steroid hormone secretion, prostaglandin release and myometrial contraction is fully established? Is the localconcentration of prostaglandin F,, regulated by control of synthesis, releaseor rate of destruction? Where is prostaglandin F,, formed in relation to myometrial contraction? Is its action necessarily linked to that of oxytocin? Whatcontrols cervical dilatation, and what determines the different responses of thecervix and body of the uterus to prostaglandins?The symposium programme is designed to survey knowledge first in thosespecies, the goat and sheep, in which it appears-perhaps superficially-to bemost complete, and then to proceed to other species. In small polytocouslaboratory animals it is not certain how the mechanisms so beautifully demonstrated in the sheep and goat apply. And when we come to the primate, andespecially man, the first impression has been that the fetus may not be to thesame extent in control of the duration of gestation. Indeed the wide, and perhapswidening, range of the natural time of delivery, as compared with other speciesis a matter of practical concern.There are two other comments to make before we get on with the business inhand. Nothing could be worse, it would seem, for the fetus in utero, than to besubjected repeatedly to ineffective uterine contractions. So it would not besurprising if the systems which operate to control parturition are designed as acascade with positive feedback, in which once the lock is undone or the firststep taken, parturition must inevitably proceed. And it would be a logical

4G.S. DAWESfeature of reproductive design if the initiation were under fetal control, so thatthe other systems necessary for postnatal survival were normally mature beforebirth. In this sense fetal autonomy would be a necessary feature of development.ReferencesBINNS,W., JAMES,L. F. & SHUPE,J. L. (1964) Toxicosis of Veratrum califi,rnicum in ewes andits relationship to a congenital deformity in lambs. Ann. N . Y . Acad. Sci. IZI, 571-576BUTLER,N. R. & BONHAM,D. G. (1963) Perinatul Mortality, Livingstone, EdinburghCiba Foundation (1969) Progesterone: its regulatory effect on the myometrium (Ciba Found.Study Group 34), Churchill, LondonCiba Foundation (1969) Foetal Autonomy (Ciba Found. Symp.), Churchill, LondonHOLM,L.W. (1963) in Initiation o f l a b o r , pp. 159-166, USPHS Publication No. 1390, Washington, D.C.HOLM,L.W. & SHORT,R.V. (1962) Progesterone in the peripheral blood of Guernsey andFriesian cows during prolonged gestation. J . Reprod. Fertil. 4, 137-141LIGGINS,G.C. (1969) The foetal role in the initiation of parturition in the ewe, in FoetalAutonomy (Ciba Found. Symp.), pp. 218-23 1, Churchill, LondonLIGGINS,G.C., KENNEDY,P.C. & HOLM,L.W. (1967) Failure of initiation of parturitionafter electrocoagulation of the pituitary of the fetal lamb. Am. J. Obstet. Gynecol. 98,1080-1086LOVATT-EVANS,C. (ed.) (1936) Starling’s Principles of Human Physiology, 7th edn, Churchill,LondonMALPAS,P. (1933) Postmaturity and malformations of the foetus. J. Obstet. Gynaecol. Br. Emp.40, 1046-1053

Parturition in the sheepG. C. LICGINS, R. J. FATRCLOUGH, SUSAN A. GRIEVLS,CHRISTINE S. FORSTER and B. S. KNOXPorrgraduufe School of Obstetrics and Gynaecology, University of AiicklanciParturition in sheep is initiated by a sharp rise in the rate of secretionof cortisol by the fetal adrenal. Increased secretion is due partly to enhancedresponsiveness to corticotropin (ACTH) and partly to increased fetal concentrations of corticotropin. Cortisol acts on placental enzymes active in the biosynthesis of oestrogens from progesterone. Thus placental secretion of oestrogenincreases and that of progesterone decreases. This change in the ratio of oestrogen :progesterone, particularly the rise in oestrogen, stimulates release of prostaglandinF,, (PGF,,) from the maternal placenta and to a lesser extent from the myometrium. PGF,, enhances the myometrial response to oxytocin and, after alatent period, stimulates contractions. The onset of parturition is normallyassociated with softening of the cervix, the mechanism of which is uncertain.Uterine contractions in the presence of a distensible cervix lead to parturition.AbstractThis paper reviews existing knowledge of the system by which labour is initiatedin sheep. The system begins with the hypothalamus of the fetus and ends withthe smooth muscle and collagen of the maternal uterus. Between these limits acomplex chain of events, including amplification steps and positive feedbackloops, ensures that, once started, progress t o completion is inexorable andefficient. Fetal maturational events linked to this system as by-products, althoughvital to the success of parturition in terms of neonatal survival, are reviewedelsewhere (Liggins 1977). Certain aspects of the system are described in detailby others in this symposium (see Nathanielsz et al. pp. 73-91) and will beconsidered only briefly in this paper. For convenience, the system is subdividedaccording t o hormones rather than organs as is more usual.CORTICOTROPIN (ACTH)Hypophysectomy in the fetus (Liggins et al. 1967; Comline et al. 1970;Bosc 1972; Barnes et al. 1975) but not in the mother (Denamur & Martinet 1961 ;

6G. C . LIGGINS ET AL.Bosc 1972) prevents parturition. Of the pituitary hormones that are lackingafter hypophysectomy, the one most favoured as causing the failure of parturition is corticotropin (ACTH). However, no experimental proof has been reported of the parturitional mechanism being restored in hypophysectomizedfetuses infused with corticotropin at rates that maintain physiological levels.The concentration of corticotropin in fetal plasma falls to low levels ( IOpg/ml)after hypophysectomy (Johnson et al. 1975), as would be expected unless theplacenta were a significant source of corticotropin. This observation does notexclude the possibility that absence of another pituitary hormone, either aloneor in conjunction with corticotropin, mediates the effects of hypophysectomy.Intraperitoneal infusion of I mg each of ovine somatotropin (growth hormone),thyrotropin, lutropin (luteinizing hormone), follitropin (follicle-stimulatinghormone) and prolactin into a fetal lamb daily for eight days failed to inducelabour, and the same mixture of ovine pituitary hormones together with 0.1 mgcorticotropin did not shorten the latent period from the start of infusion todelivery in three fetuses compared to others infused with corticotropin alone(Liggins 1969). These observations suggest that pituitary hormones other thancorticotropin do not contribute to the onset of parturition, but similar experiments using the intravenous rather than the intraperitoneal route need to bedone since nothing is known of the rate of absorption of pituitary hormonesother than corticotropin.The success of inductions of premature parturition with fetal infusions ofcorticotropin (Liggins 1969; Bassett & Thorburn 1973) led to the belief thatspontaneous parturition at term follows adrenal stimulation caused by theincreased concentrations of corticotropin in the fetal plasma that are consequentupon increasing activity of the hypothalamus and pituitary. Recent measurements of corticotropin in fetal plasma which have shown that the prepartum risein cortisol precedes any rise in corticotropin concentrations (Rees et al. 1975;Jones et al. 1977a) point to the need to revise this hypothesis. As will be discussedbelow, emphasis is now placed on a heightened responsiveness of the adrenalcortex to corticotropin. Nevertheless, it is clear that the fetal hypothalamus andpituitary play essential roles in initiating parturition. Failure of parturition afterstalk section (Liggins et al. 1973) or hypophysectomy could be interpreted asdemonstrating only a permissive function of corticotropin. There is evidence,however, that the pituitary is more actively involved. Administration of cortisoldepresses corticotropin to undetectable concentrations in the plasma of fetusesof less than 136 days (Thomas & Pierrepoint 1975), yet at term the initial risein cortisol concentrations is not associated with a fall in corticotropin. Furthermore, the subsequent further rise in cortisol is accompanied by rising concentrations of corticotropin (Rees et al. 1975). This suggests that the threshold of

7PARTURITION I N THE SHEEPnegative feedback of cortisol on the hypothalamus and pituitary may rise nearterm, a change that could be essential to full development of the prepartunisurge of adrenal activity. The sharp fall in cortisol concentrations after birth mayindicate a return of the threshold to a lower set-point.A sustained experimental stimulus to corticotropin secretion has not beendescribed yet. Short periods (60 min) of hypoxaemia raise plasma corticotropinfrom basal values of about 100 pg/nil to 700-800 pg/nil (Jones et al. 19766).Repeated daily periods of hypoxaeinia are associated with a gradual increase i nthe fetal cor t i cost ero i d response but d o not i n d Lice pre m a t u re 1a bo u r, probablybecause of the transient nature of the stimulus.CORTl SOL,The sharp prepartum rise in cortisol concentrations in the fetus, first describedby Bassett & Thorburn ( I969), has been confirmed by several other workers andis known to be due mainly to increased production of cortisol by the fetus(Beitins et al. 1970; Nathanielsz e t a / . 1972; Liggins e t a / . 1973), and partly toincreased concentrations of corticosteroid-binding globulin (Fairclough &Liggins 1975). Increased secretion of cortisol is caused mainly by enhancedresponsiveness of the adrenal to corticotropin rathcr than by higher circulatingLO35307 2532- 20a s 1510560504030DAYS2010"651321BEFORE PARTURITIONFIG.1. Response at various gestational ages to an intravenous fctal infusion of syntheticcorticotropin (Synacthen), 10 Fgimin for 60 min. Solid bar, fetal carotid plasma concentrationof cortisol before Synacthen; opcn bar, increment in cortisol level at 60 min. Individual sheeparc identified by the no. in parcntheses abovc the bars. Note change in scale of abscissa.

8G. C. LIGGINS ET AL.concentrations of corticotropin. The immature adrenal cortex shows littleresponse to short periods of exposure to corticotropin either in vitro (Madill &Bassett 1973; Wintour et al. 1975) or in vivo (Fig. 1). Near term, responsivenessincreases markedly for reasons that are only partly known and which DrNathanielsz will consider further (see pp. 73-91); briefly, several factors havebeen suggested as responsible :( I ) Increase in cortical mass (Comline & Silver 1961). This may be aconsequence as much as a cause of enhanced response.(2) Maturation of the enzymes 1lp- and 17a-hydroxylase (steroid 1 lp- and17a-monooxygenase; EC 1.14.15.4 and EC 1.14.99.9) (Anderson et al. 1972),which could be rate-limiting in cortisol biosynthesis in the immature fetaladrenal. Wintour et al. (1975) have recently shown that fetal adrenals in vitroshow a marked response to corticotropin before day 80 of pregnancy andsubsequently become less responsive. Their observation is not consistent withdelayed enzyme maturation being the cause of impaired response later inpregnancy. Madill & Bassett (1973) confirmed a relative deficiency of 17ahydroxylation in vitro but found no evidence that 1 1P-hydroxylation was ratelimiting. The relative proportions of cortisol, corticosterone and 11-deoxycortisol in the plasma of immature fetuses during prolonged infusions ofsynthetic corticotropin (Synacthen) do not suggest a major deficiency of eitherenzyme (Table 1).(3) Enhanced uptake of corticotropin by the cortex, possibly due to horTABLE 1Response of fetal plasma corticosteroids to continuous fetal infusion of synthetic corticotropin(Synacthen), 0.12 mg/24 h (Fairclough & Liggins 1977)Fetus Gestational age(days/ Hours beforeparturition CorticosteroneIwlml) 71.51.o0.81.41.1a- not measured.- -Deoxycortisol(nglml)Cortisol(ngiml) - .015.29.931.648.764.762.3

9PARTURITION IN THE SHEEPnional stimulation of formation of receptor sites. Incubation of pituitary tissuewith adrenals does not increase the response to corticotropin, which suggeststhat anterior pituitary hormones apart from corticotropin are not involved(Madill & Bassett 1973). However, the short period of incubation may beinsufficient to stimulate synthesis of additional receptor sites. Daily hypoxaemicepisodes that transiently raise fetal concentrations of corticotropin lead to aprogressive increase in fetal adrenal response (Jones et al. 1977b) which couldbe caused directly by corticotropin or, alternatively, by cortisol. The secondpossibility is supported by our finding of increased response after a fetal infusionof dexamethasone for 48 h (Fig. 2), but any other hormone such as oestradiol-17Por prolactin that may be raised by dexamethasone could hc responsible.Ia.- 6 11111niFIG.2. Response to an intravenous infusion of Synacthen, 10 pg/rnin for 60 rnin, in fourfetuses before and after infusion of dexarnethasone, 1 rng/24 h. Gestational age of fetus atstart of infusion shown in parentheses. See legend to Fig. 1 for key.The prepartum surge of cortisol in the fetus is accompanied by falling concentrations of progesterone in uterine vein blood and rising concentrations ofconjugated and unconjugated oestrone and oestradiol-17P in both maternal andfetal blood (Thorburn et al. 1972; Currie et al. 1973). These changes can bereproduced precisely by infusion of the glucocorticoid, dexamethasone, into thefetus (Currie et al. 1973); strong evidence is thus provided for a causal relationship between the cortisol surge and the dramatic changes in the production ofoestrogen and progesterone. There is no evidence at present that the action ofcortisol is mediated through mechanisms othci than those related to themetabolism of progesterone and oestrogen.

10G . C . LIGGINS ET AL.PROGESTERONE AND OESTROGENHormone productionThe placenta is the major source of progesterone in the sheep (Linzell & Heap1968) and the relative concentration of progesterone in peripheral and inuterine venous blood in late pregnancy is about 1 :5. There is evidence that theplacenta is the major source also of oestrogen. The concentration of oestronesulphate in uterine vein blood is about four times higher than that in jugularvein blood (Flint et al. 1976). Removal of the maternal adrenals and ovariesreduces concentrations of oestradiol-17P by only 24-32 % and does not preventthe prepartum rise (Thompson & Wagner 1974). Furthermore, the placenta hasthe capacity to synthesize oestrogens from C,, steroid precursors in vitro(Ainsworth & Ryan 1966).Although the patterns of progesterone and oestrogen concentrations throughout pregnancy have been well known for several years (Bassett et al. 1969;Challis 1971), the mechanism by which the fetal adrenal influences thesepatterns has been determined only recently. Earlier views favoured the conceptof a fetoplacental unit in which oestrogen synthesis was dependent on precursors formed in the fetal and maternal adrenals. Evidence accumulated thatwas not consistent with these views. Induction of labour with dexamethasoneis associated with concentrations of oestrogen as high as those observed in termlabour (Flint et al. 1976), yet dexamethasone fully suppresses adrenal functionas judged by the plasma cortisol concentration (Thomas & Pierrepoint 1975).Oestrogen concentrations are similarly increased by dexametha onein adrenalectomized fetuses (Flint et al. 1976). Evidence is now available to implicate theterm placenta in the total synthesis of oestrogen without the need for a precursorfrom an extrapl

ISBN Elsevier North-Holland, Inc., 0-444-1 5255-5 Published in March 1977 by Elsevier/Excerpta Medica/North-Holland, P.O. Box 21 1, Amsterdam and Elsevier North-Holland Inc., 52 Vanderbilt Avenuz, New York, N.Y. 10017. Suggested series entry for library catalogues: Ciba Foundation Symposia.